West Nile Virus (WNV) is an emerging mosquito-borne human and animal pathogen that has caused outbreaks of fatal encephalitis in Europe, Asia, the Middle East, and most recently, the United States. Little is known about the pathogenesis of WNV infection and the immune system response that prevents extension into the central nervous system (CNS) in most hosts. Recently, using a mouse model of WNV encephalitis, we have demonstrated that a deficiency of antibody or complement proteins leads to a disseminated, fatal infection. Based on these observations, the proposed research plans to directly determine how B cells, antibody and complement orchestrate a protective immune response against WNV. In Specific Aim 1, our in vivo mouse model of WNV infection will be used to determine the protective role of natural and specific IgM against WNV in limiting the early phase of dissemination and the subset of B cells that mediate this response. In Specific Aim 2, the mechanism by which complement primes the adaptive immune response against WNV will be characterized. In Specific Aim 3, the role and mechanism by which complement receptor 1 and 2 trigger adaptive immunity against WNV will be investigated. The identification of specific mechanisms for controlling early dissemination of WNV infection and triggering long-term protection will enhance our understanding of viral pathogenesis and the epidemiology of WNV-induced disease, and possibly provide a rationale for therapeutic intervention.